Multicenter Study of Nonadherence to Self-Injectable Biologic Therapy in Patients With Inflammatory Bowel Disease: Risk Factors and Outcomes

Background and Aims This study aimed to evaluate adherence to subcutaneous biologic therapy and impact of nonadherence including risk factors and outcomes in academic centers with integrated specialty pharmacies for patients with inflammatory bowel disease (IBD). Methods This was a multicenter, retrospective cohort analysis of patients aged ≥18 years receiving care in 3 tertiary care outpatient IBD clinics with integrated specialty pharmacies. Subjects were prescribed injectable anti-TNF therapy (adalimumab, certolizumab, golimumab) or anti-IL 12/23 therapy (ustekinumab) with at least 3 consecutive prescription claims. The primary outcomes were medication possession ratio (MPR), percent achieving optimal adherence (MPR > 0.86); in addition, we sought to verify a prior risk factor model including smoking status, narcotic use, psychiatric history, and prior biologic use. Secondary outcomes included emergency department visits (ED) and IBD-related hospitalizations. Statistical analysis was performed using Wilcox rank sum test, Pearson’s Chi-squared test, and logistic regression model as an unordered, factor variable to flexibly estimate the probabilities of adherence. Results Six hundred eight subjects were included. Overall median MPR was 0.95 (interquartile range 0.47, 1) and adherence was 68%–70%. When the number of risk factors for nonadherence increased, the likelihood of nonadherence increased (P < .05). In unadjusted and adjusted analysis, nonadherence increased the likelihood of ED visits [rate ratio 1.45 (95% confidence interval 1.05, 1.97)] and hospitalizations [rate ratio 1.60 (95% confidence interval 1.16, 2.10)]. Conclusion Academic centers with integrated pharmacies had high adherence. Prior risk factors for nonadherence remained significant in this multicenter model. Nonadherence was associated with higher likelihood of hospitalizations and ED visits.


Introduction
I nflammatory bowel disease (IBD) is a chronic in- flammatory disease of the gastrointestinal tract that includes Crohn's disease (CD) and ulcerative colitis (UC). 1 Disease exacerbation is often associated with emergency department (ED) visits, hospitalizations, change in maintenance medication, and steroid use to alleviate symptoms.Prolonged inflammation due to inadequately controlled disease can cause irreversible damage and complications; thus, induction and maintenance of disease remission is critical to avoid negative clinical outcomes and increased healthcare costs.3][4][5] Maintaining optimal adherence is imperative to achieving durable clinical benefit.Nonadherence to medications increases healthcare costs, risk of disease flare, and antidrug antibody formation for anti-TNF therapies. 6,7ccurate measurement of adherence is essential to developing strategies to improve adherence; therefore, objective measures of adherence, such as medication possession ratio (MPR) are important and often used in pharmacy claims data. 8A large nationally representative claims database study of patients prescribed self-injectable anti-TNF medications found that patients with an MPR >0.86 for adalimumab and 0.87 for certolizumab had significantly lower risk of disease flare. 9This threshold can therefore be used to identify nonadherent patients.
Identifying patients at risk for nonadherence is important to develop strategies to improve adherence.0][11][12][13][14][15][16][17] Previous analysis evaluated risk factors for nonadherence (MPR < 0.86) to self-injectable biologic medications.This study found that, in a multivariable regression model, Medicaid insurance status and Crohn's disease increased nonadherence.Also, several easily clinical identifiable factors in univariate analysis were significant (specifically smoking, narcotic use, psychiatric history, and prior biologic therapy).When the number of these risk factors for a particular patient increased, the likelihood of nonadherence significantly increased. 18As this was a singlecentered study with limited demographic diversity, the generalizability of these findings was limited.Therefore, the aim of this analysis was to evaluate adherence across several academic centers with integrated specialty pharmacies, to assess if previously identified risk factors for nonadherence remained significant across several diverse IBD centers and to evaluate outcomes associated with nonadherence.

Methods
This was a multicenter, retrospective cohort analysis of patients aged !18 years receiving care at 1 of 3 tertiary care outpatient clinics (Vanderbilt University Medical Center, University of Maryland, and University of Minnesota) for either active CD or UC.Study period was from January 1, 2018 through December 31, 2019 for center 1 and March 2018 to March 2019 for center 2 and August 2018 to July 2020 for center 3 (available data from the specialty pharmacies were slightly different secondary to differing reporting strategies per center at the time of data collection).Patients prescribed a subcutaneous anti-TNF therapy (adalimumab, certolizumab, golimumab) or anti-IL 12/ 23 therapy (ustekinumab) and receiving medication through the center's integrated specialty pharmacy (to permit access to pharmacy claims data) were included.Patients with less than 3 specialty prescription claims or a change in pharmacy during the study period were excluded, as these confounders would limit the ability to accurately calculate medication adherence. 8Patients were followed until end of study date, medication was stopped, or loss of follow-up occurred.Patients who changed to a new biologic only had the first biologic evaluated.
Baseline disease characteristics, surgical history, previous biologic therapy, current smoking status, concomitant therapy for IBD, and active narcotic prescription at the time of biologic initiation were extracted from the electronic medical record (EMR).Insurance status was assessed at baseline.Psychiatric comorbidity was defined as a documented diagnosis in the EMR (including depressive disorders, anxiety disorders, bipolar disorders, and/or psychotic disorders).Prescription claims data extracted from the specialty pharmacy database were analyzed to identify patient-specific medication dispensing dates and payment methods.Data were managed using Research Electronic Data Capture (REDCap). 19,20IBD-related emergency department visits and hospitalizations in followup were extracted from the EMR.
The primary outcome of medication adherence across several academic centers with integrated specialty pharmacies was assessed using MPR, calculated as the total sum of days' supply for each medication refill divided by the number of days in the observation period and was calculated from fill dates using the same formula for all centers. 9This adherence measurement is accurate regardless of dosing strategies for adalimumab, certolizumab, and golimumab as it accounts for prescription required days' supply.For ustekinumab, since the prescribed day supply often exceeds the 30-day supply limit mandated by some third-party benefit managers at the time of a prescription claim, we used the prescribed day supply as noted in the EMR prescription for the denominator.The MPR calculation was capped at one.We defined nonadherence as MPR <0.86 based on prior research. 9econdary outcomes included determination of the effect of prior identified risk factors (smoking, narcotic use, psychiatric history, and prior biologic use) on nonadherence in a multicenter cohort.Other secondary outcomes included the impact of nonadherence on number of ED visits and hospitalizations.Unadjusted association between adherence or disease status and prespecified risk factors were tested using either the Wilcox rank sum test (continuous variables) or Pearson's Chisquared test (categorical variables).Unadjusted and adjusted odds ratios with corresponding 95% confidence intervals (CIs) were estimated using univariable and multivariable logistic regression, respectively.Initial risk factors were prespecified and included in the models regardless of statistical significance.All relevant risk factors were reduced to a score (0-4) by summing 4 binary risk factors: prior biologic use, current narcotic use, smoking, and any psychiatric history.These variables were chosen as they had significance in prior literature and our prior work.The risk score was then included in a logistic regression model as an unordered, factor variable to flexibly estimate the probabilities of adherence for subjects with risk scores of 0, 1, 2, 3, or 4. All statistical analyses were performed using the R statistical package.

Ethical Considerations
This was a retrospective study with no significant ethical considerations.

Results
Six hundred eight patients were included (center 1, originator center: n ¼ 460, center 2: n ¼ 81, and center 3: n ¼ 67).Overall median days followed was 903 days (interquartile range 187, 3900 days) and did not differ between centers.Table 1 summarizes patient characteristics.Generally, patients had similar characteristics across the 3 centers; however, centers 2 and 3 had more non-White patients and patients with Medicaid insurance.Center 3 had more patients with UC and less patients who had previous surgery, been on prior biologics, required narcotics, or had perianal or fistulizing disease, suggesting a patient population with less severe disease.
Seventy percent of the population was adherent (MPR > 0.86).The median MPR was high at 0.95 (interquartile range 0.47, 1).MPR and adherence rates were similar between centers as detailed in Table 2. Univariate analysis revealed the following were associated with nonadherence: female sex, noncommercial health insurance, and positive smoking status.Disease types in CD (perianal disease or fistulizing disease) were not significant (Table 3).
In multivariable logistic regression, patients with Medicaid insurance status had an increased risk of nonadherence (Figure 1).When the number of risk factors for nonadherence increased, the likelihood of nonadherence increased (P < .05)(Figure 2).Adherence (MPR > 0.86) was 74% if patients had 0-1 risk factors, decreasing to 66% when 2 risk factors were present, 64% when 3 risk factors were present, and only 48% if 4 risk factors were present (P < .05).

Discussion
We found high adherence rates (70%) and high median MPR (0.95) for IBD patients on self-injectable biologic medications.This was similar across all centers, geographic regions, and patient demographics.Nonadherence significantly increased the risk of ED visits and hospitalizations.These findings highlight the impact of biologic adherence on direct patient outcomes and healthcare costs.We additionally validated previously identified risk factors in a multicentered cohort.Patients with increasing number of nonadherence risk factors had substantially lower adherence.Those with 4 risk factors had less than 50% adherence.Adherence rates to self-injectable biologic medications for patients in this cohort were significantly higher than nationally reported adherence rates in IBD patients. 92][23][24][25] Our findings add additional support to the benefit of this integrated specialty pharmacy team model, which may improve adherence through close co-management with the clinical IBD team.Health system specialty pharmacy teams perform patient outreach on a regular basis to assess for medication-related issues and try to improve adherence.The specialty pharmacy team also manages navigation of the insurance approval process which can be a very difficult aspect of continuing biologic therapy for patients. 26It is possible that other areas of   support from tertiary care centers for inflammatory bowel disease could contribute to high adherence for patients.However, even within our study with high adherence, 30% of patients did not meet the adherence threshold of MPR >0.86.Understanding risk factors for nonadherence can help inform patient-centered care delivery models for patients on subcutaneous biologic medications.A systematic review showed risk factors for nonadherence to anti-TNF therapy include female sex, smoking, anxiety, and moodiness. 17Also, a recent study from the national Manitoba cohort with prospective data collection showed that presence of anxiety and depression increases the likelihood of anti-TNF discontinuation. 10Our findings supplement prior work and further highlight the importance of an individual's psychiatric history when selecting appropriate IBD management strategy.Patients who have a high probability of nonadherence or discontinuation from biologic therapy may need closer monitoring and aggressive mental health support.In addition to psychiatric history, we found other patient factors such as smoking, narcotic use, and prior biologic use increases nonadherence.Other studies suggest these factors play a role in poor IBD outcomes in general.For instance, smoking is independently associated with poor IBD outcomes. 27Narcotic use and psychiatric disorders are associated with higher healthcare utilization. 280][31] Factors that may be out of a patient's control, such as Medicaid insurance status, have been associated with nonadherence. 32These patients may have more restricted access to care and economic limitations. 33It is unlikely that any single factor is itself causal to nonadherence but rather reflects a complex psychosocial environment that can lead to nonadherence.Our multicenter study confirms there is a synergistic or cumulative effect of these factors resulting in nonadherence.
Our findings have important considerations for the cost of care for IBD patients on self-injectable biologic medications.We showed that nonadherence significantly increased the likelihood of IBD-related ED visits and hospitalizations.A recent study looking at the healthcare costs associated with patients with IBD found that patients with one ED visit had costs more than twice as high as patient without ED visits. 34Improving medication adherence for moderate to severe IBD is an easily definable target for healthcare systems to improve cost and enhance clinical outcomes.The high adherence data in this study lend support to the patient-centered multidisciplinary care.Other data have shown that integrated care models for patients with IBD can improve clinical outcomes including decreasing ED visits and hospitalizations. 35,36trengths of this study include a multicenter approach with significant diversity in geographic location, race, and insurance status to allow for validation of our previous work.In addition, we used an objective marker of adherence across centers.However, there is limitation to using MPR, as it does measures medication acquisition and not direct administration.However, it is unlikely for a patient to continue obtaining a self-injectable biologic medication over more than a 6-month period without administering the medication consistently.MPR could not be assessed by patients outside of academic center specialty pharmacy as access to adherence data is not freely given by national contracting specialty pharmacies.Limiting to 3 or more claims to ensure stability on medication could miss those who would be most at risk for nonadherence.We also were limited to EHR data which may have missed some clinical outcomes including ED visits external to the related hospital system.We also did not have data regarding health literacy, education status, or specific reason for nonadherence such as disease activity at time of missed doses.Our study period did not allow for evaluation of newer mechanisms such as oral small molecule medication.

Conclusion
In conclusion, our study shows high adherence rates for patients receiving self-injectable biologic medications who fill from an IBD center specialty pharmacy, exceeding previously reported national adherence rates.We validated a model demonstrating that increasing identifiable risk factors (smoking, narcotic use, psychiatric history, and prior biologic use) increases the likelihood of nonadherence.Patients with Medicaid insurance remain at a higher risk of nonadherence in this multicenter model.Nonadherence increases the probability of IBD-related ED visits and hospitalizations.All healthcare industry stakeholders including healthcare systems, manufacturers, and third-party benefit providers need to understand the importance of improving patient adherence.Decreasing barriers to self-injectable medication acquisition, increasing direct patient interaction with integrated pharmacy teams, and comprehensive patient education are a start to improving patient adherence.In addition, we propose that enhanced care pathways for patients with risk factors for nonadherence would improve adherence and outcomes.

Figure 1 .
Figure 1.Multivariable regression analysis for risk factors for adherence in all patients with inflammatory bowel disease from 3 tertiary care IBD centers started on a self-injectable biologic medication.

Figure 2 .
Figure 2. The overall probability of nonadherence (MPR < 0.86) for patients started on a self-injectable biologic medication from 3 tertiary care IBD centers significantly increases as the number of risk factors (prior biologic use, smoking, narcotic use, and psychiatric history) increase.

Figure 3 .
Figure 3.The overall likelihood of ED visits and hospitalizations increases if patients were nonadherent to self-injectable biologic medication (MPR < 0.86).

Table 1 .
Demographics and Clinical Characteristics of Patients With Inflammatory Bowel Disease on Subcutaneous Biologic Therapy Across IBD Centers

Table 2 .
Medication Possession Ratio and Adherence Rates of Patients With Inflammatory Bowel Disease on Subcutaneous Biologic Therapy Across IBD Centers a Medication Possession Ratio.

Table 3 .
Univariate Analysis for Risk Factors for Nonadherence to Self-Injectable Biologic Medications in Patients With IBD